An important attribute of a drug delivery system is its ability to allow for spatial and temporal regulated drug release, thereby minimizing side effects and improving therapeutic efficacy of conventional pharmaceuticals. Iron oxide nanoparticles (NPs), specifically Fe3O4 nanoparticles, possess many appropriate qualities that make them a viable choice for drug delivery. Fe3O4 NPs are biocompatible (Kievit, F. M., et al., Accounts of Chemical Research 2011, 44 (10), 853-862), have low cytotoxicity (Bulte, J. W. M., et al., NMR in Biomedicine 2004, 17, 484-499), and provide multiple means for surface modification. Though these attributes are needed in a drug delivery vehicle, there are multiple different NPs that possess similar qualities including gold and silica. Fe3O4 is set apart from these NPs due to its paramagnetic or superparamagnetic (SPM) qualities (Yang, C., et al., Chemical Communications 2011, 47, 5130-5141). The SPM properties of Fe3O4 NPs have been used for a variety of applications. A basic utilization of SPM capability is to induce non-invasive hyperthermia within cancer cells. Alternating electromagnetic field (AMF)-induced Fe3O4 NPs heat body tissue to temperatures as high as 45° C., and this causes cell death. In addition, when functionalized either by ionic interactions or through entrapment via a polymer gel coating, drugs can be guided to tumor regions through the use of a magnet, as first demonstrated by Meyers in 1963 (Meyers, P. H., et al., American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine 1963, 90, 1068-1077). Through more advanced methods, Fe3O4 NPs are now extensively functionalized with complex delivery mechanisms and can be directed by taking advantage of tumor folate receptors (Kim, J., et al., Advanced Materials 2008, 20, 478-483, Zhang, Z., et al., Biomaterials 2007, 28 (10), 1889-1899, Zhang, L., et al., International Journal of Pharmaceutics 2004, 287 (1-2), 155-162). Finally, iron oxide also can be used as a magnetic resonance imaging contrast agent, so delivery systems based on this material can be visualized (Lee, J. E.; et al., Journal of the American Chemical Society 2010, 132, 552-557).
Some of the most common methods of functionalization or attachment of drug payloads to Fe3O4 NPs involve the use of ionic attraction (Nantz, M. H., et al., PCT Int. Appl. 2011, WO 2011049972 A1 20110428), the addition of a mesoporous silica shell around the Fe3O4 NPs followed by further functionalization of the silica (Meng, H., et al., A. E., ACS Nano 2010, 4 (8), 4539-4550, Lin, Meng M., et al., Nano Reviews 2010, 1, 4883) or the use of a polymer coating around the Fe3O4 NPs (Yu, M. K., et al., Angewandte Chemie International Edition 2008, 47 (29), 5362-5365, Rahimi, M., et al., Nanomedicine: Nanotechnology, Biology, and Medicine 2010, 6, 672-680). Once the NPs reach target (e.g., cancerous) tissue, a release mechanism is initiated so that the drug payloads are available only to the target tissue. One of the most common release methods involves use of a pH sensitive trigger, such as when using a hydrazone linkage (Aryal, S., et al., Journal of Materials Chemistry 2009, 19, 7879-7884). For example, when the loaded NP enters into a tumor, the reduced pH of the tumor can hydrolyze the hydrazone linkage to unmask the drug (a carbonyl-based drug). Another method of release is photochemical. By adding a photolabile group into a linker, usually an aromatic ring with a nitro-group ortho to a leaving group, the drug can be released upon exposure to a specific wavelength of light (Choi, S. K., et al., Bioorganic & Medicinal Chemistry 2012, 20, 1281-1290).
Another method to release the drug involves the use of an alternating electromagnetic field (AMF). An AMF, similar to an AC current, switches the poles of the magnetic current at a quick pace, and this causes resident iron oxide NPs to heat as they struggle to stay aligned with the applied magnetic field (Carrey, J., et al., Journal of Applied Physics 2011, 109, 083921). AMF-mediated drug delivery has a distinct advantage over the pH sensitive linker approach in that drug release relies on a controllable external stimulus whereas the acid labile linker requires a stimulus within the patient that cannot be easily controlled. If the tumor is not sufficiently acidic, then the linker-bound drug will not be released. In the same way, if certain healthy cells happen to be overly acidic, then the drug is released and can exert its pharmacological effect on healthy cells. In contrast, AMF exposure allows for the controlled release in a specific region and at a specific time without the need for precise, and often unpredictable, internal conditions. Thus AMF-mediated delivery systems offer the advantages of spatial and temporal control.
Despite the advantages in controlled release using an AMF trigger, many present NP drug delivery systems have a problem of premature drug release (i.e., leakage). In these instances, drugs are slowly released prior to application of the external stimulus. This is largely due to the inability of the drugs in these delivery systems to be covalently retained until the stimulus is applied. For example, AMF-induced NP heating commonly is used to reduce ionic interactions and/or hydrogen bonding interactions (Biswas, S. Functionalized Nanoparticles for AMF-Induced Gene and Drug Delivery. University of Louisville, Louisville, Ky., 2011), or to cause a polymer shell to squeeze out the drug payload (Liu, T.-Y., et al., Langmuir 2008, 24, 13306-13311) or to expand and allow the drug payload to diffuse away (Liu, J., et al., Journal of Physical Chemistry C 2010, 114, 7673-7679). In these cases, the ambient heat or biological milieu of a living system can reduce the ionic/hydrogen bonding interactions between NP and drug, or cause polymer contractions or expansions. Premature drug release occurs since the drug is not covalently attached to the NP carrier.
Patent application publication WO2014/124329 describes therapeutic magnetic nanoparticles which include a therapeutic agent connected to a magnetic nanoparticle through a linker and functional group. These nanoparticles include a linker that will undergo an intramolecular cyclization with the functional group thereby releasing the therapeutic agent from the magnetic nanoparticle core.
There is a need for alternative drug delivery systems with reduced premature release of its drug payload and that can optionally target the drug spatially, temporally, or both spatially and temporally.